The ability of the mammalian immune system to recognize “self” versus “non-self” antigens is vital to successful host defense against invading microorganisms. “Self” antigens are those which are not detectably different from an animal's own constituents, whereas “non-self” antigens are those which are detectably different from or foreign to the mammal's constituents. A normal mammalian immune system functions to recognize “non-self antigens” and attack and destroy them. An autoimmune disorder such as for example, rheumatoid arthritis, insulin-independent diabetes mellitus, acquired immune deficiency syndrome (AIDS), multiple sclerosis, and the like, results when the immune system identifies “self” antigens as “non-self”, thereby initiating an immune response against the mammal's own body components (i.e., organs and/or tissues). This creates damage to the mammal's organs and/or tissues and can result in serious illness or death.
Predisposition of a mammal to an autoimmune disease is largely genetic; however, exogenous factors such as viruses, bacteria, or chemical agents may also play a role. Autoimmunity can also surface in tissues that are not normally exposed to lymphocytes such as for example, neural tissue. When a tissue not normally exposed to lymphocytes becomes exposed to these cells, the lymphocytes may recognize the surface antigens of these tissues as “non-self” and an immune response may ensue. Autoimmunity may also develop as a result of the introduction into the animal of antigens which are sensitive to the host's self antigens. An antigen which is similar to or cross-reactive with an antigen in an mammal's own tissue may cause lymphocytes to recognize and destroy both “self” and “non-self” antigens.
It has been suggested that the pathogenesis of autoimmune diseases is associated with a disruption in synthesis of interferons and other cytokines often induced by interferons (Skurkovich et al., Nature 217:551-552, 1974; Skurkovich et al., Annals of Allergy, 35:356, 1975; Skurkovich et al., J. Interferon Res. 12, Suppl. 1:S110, 1992; Skurkovich et al., Med. Hypoth., 41:177-185, 1993; Skurkovich et al., Med. Hypoth., 42:27-35, 1994; Gringeri et al., Cell. Mol. Biol. 41(3):381-387, 1995; Gringeri et al., J. Acquir. Immun. Defic. Syndr., 13:55-67, 1996). Cytokines are substances produced in different cell territories, including immune and nerve cells, which communicate with and affect the action of cells. In particular, gamma interferon plays a significant pathogenic role in autoimmune dysfunction. Gamma interferon stimulates cells to produce elevated levels of HLA class II antigens (Feldman et al., 1987, “Interferons and Autoimmunity”, In: IFN (, p. 75, Academic Press). It is known that gamma interferon participates in the production of tumor necrosis factor (TNF), and it is also known that TNF also plays a role in stimulation of production of autoantibodies. In view of this, therapies to modulate these cytokines have been developed. Clinical success in treating several autoimmune diseases using antibodies to gamma interferon has been reported (Skurkovich et al., U.S. Pat. No. 5,888,511).
Viral diseases pathogeneses may develop not by the virus itself but from the interferon induced by the presence of the virus in infected cells and tissues. In these cases, interferon acts mostly as a pathological agent which, together with the viruses which induce interferon, exerts a pathological effect on the organism. The AIDS virus, rubella virus, herpes simplex virus 2, herpes simplex type 1, varicella, and certain other viruses and bacteria which participate in psychiatric and neurological disorders, and some chemical agents, could be considered as responsible for the induction of pathological interferon in infected patients. It is therefore possible that interferon, especially gamma interferon, can contribute to the pathology of these diseases.
The hyperproduction of gamma interferon induced by viruses and the like can also disturb the production of normal interferon. A critical step in the treatment of patients with disturbances in the production of gamma interferon can be the removal or destruction of this abnormal interferon induced by these agents. If not removed, the abnormal interferon brings on a vicious cycle of continued immune dysregulation and tissue injury. The dysregulated production of gamma interferon at different stages during genital herpes and the impaired ability of monocytic cells to respond to gamma interferon has been suggested as playing a role in the pathogenesis of recurrent genital herpes disease (Singh et al., 2003, Clin. Exp. Immunol., 133: 97-107). Further, because the production of gamma interferon is associated with interleukin-1 (IL-1) and tumor necrosis factor-alpha (TNF alpha), these cytokines may also participate in the pathological action.
Herpes is an infection caused by the herpes simplex virus (HSV). There are two types of HSV, and both can cause genital herpes. HSV type 1 most commonly infects the lips, causing sores known as fever blisters or cold sores, but it also can infect the genital area and produce sores. HSV type 2 is the usual cause of genital herpes, but it also can infect the mouth. Both HSV 1 and 2 can produce sores (also called lesions) in and around the vaginal area, on the penis, around the anal opening, and on the buttocks or thighs. Occasionally, sores also appear on other parts of the body where the virus has entered through broken skin. HSV remains in certain nerve cells of the body for life, and can produce symptoms off and on in some infected people.
Cold sores are usually caused by (HSV-1). The HSV-1 virus is part of the same virus family that causes chickenpox (varicella-zoster), shingles (herpes zoster), and genital herpes (herpes simplex virus type 2). HSV-1 infections are extremely common because the virus is very contagious and can spread through physical contact, such as kissing. Once a patient is infected with HSV-1 the virus localizes to neurons and remains either dormant or activated for the rest of the patient's life.
Common activators of HSV-1, and HSV-2 include; stress, fatigue, a cold, fever, influenza, exposure to the sun or other forms of UV rays, cold weather, hormonal changes, such as those associated with menstruation or pregnancy, and trauma at the site of the cold sore, such as shaving cuts or dental work.
Herpes lesions outbreaks generally last for 7-10 days and occur about three to four times a year. Further, herpes cold sores tend to occur in the following stages. The virus is activated from its dormancy in neurons and travels through nerve endings towards the skin, including the lips and genitals. This is usually accompanied by a tingling, itching, or burning sensation beneath the surface of the skin, usually around the site where lesions will appear. This stage of a herpes infection is known as the prodrome stage. About a day after this stage, small red bumps appear in a group, which begin to blister into a herpes lesion. After a number of days, usually about 3-4, the blisters dry up and form a yellow crust. The crust eventually falls off, leaving a red tender area. The redness subsequently fades as the immune system recognizes and attacks the herpes virus, the virus retreats to the immune privileged sites of the nervous system, and the redness fades.
Recent estimates have determined that in 45 million people in the United States ages 12 and older, approximately one out of every five members of the total adolescent and adult population, are infected with HSV-2. Further, HSV-2 accounts for approximately 90-95% of genital herpes cases and can be transmitted through oral or genital secretions.
There is no cure for herpes, either HSV-1 or HSV-2. However, three prescription drugs are available for treating herpes, especially genital herpes, as well as preventing future outbreaks. These drugs include, Acyclovir (Zovirax™), Famciclovir (Famvir™) and Valacyclovir (Valtrex™). In addition, Valacyclovir is indicated for treating cold sores. However, it is often recommended that these medications be administered at the first signs of a herpes cold sore, and their efficacy during the advanced stages of a herpes cold sore outbreak are less well known.
There exists a need for a method of treating a herpes simplex virus infection and the immune dysregulation associated with such infections. The present invention provides such methods and compositions.